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Developmental exposure to a mixture of two mechanistically distinct antiandrogens results in cumulative adverse reproductive effects in adult male rats
Citation:
HOTCHKISS, A. K., C. BLYSTONE, J. R. FURR, C. V. RIDER, AND L. E. GRAY. Developmental exposure to a mixture of two mechanistically distinct antiandrogens results in cumulative adverse reproductive effects in adult male rats. Presented at Triangle Consortium for Reproductive Biology, Durham, NC, February 23, 2008.
Impact/Purpose:
Presentation @ TCRB
Description:
Typically, toxicological studies have focused on the adverse effects from exposure to single chemicals. However, endocrine disrupting chemicals (EDCs) are detected in the environment as mixtures. Empirical evidence suggests that mixtures of EDCs with the same mechanism of action display additive effects; there are little data available on chemical mixtures with disparate cellular mechanisms. To address this issue, we treated pregnant rats with a mixture of an androgen receptor antagonist, procymidone (PRO), and a fetal testosterone synthesis inhibitor, dibutyl phthalate (DBP). We predicted that these 2 chemicals, with different cellular mechanisms, would act in a cumulative fashion to elicit adverse effects on reproductive development. Thirty-six timed-pregnant Sprague-Dawley dams (4/dosage group) were gavaged daily from gestational day 14-18 with a mixture at 100, 83, 67, 50, 33, 17, 8, 4, or 0% of the top dose of the mixture (PRO at 150 mg/kg/d and DBP at 1125 mg/kg/d). The top dose group was selected to induce a 100% malformation rate in exposed males. Neonatal males were evaluated for changes in androgen-organized anogenital distance and juvenile males were assessed for retention of nipples (an indicator of prenatal exposure to antiandrogens). Peripubertal males were assessed for onset of puberty as indicated by complete preputial separation (PPS). Adult males were evaluated for external malformations and internal malformations and reproductive tissue weights were recorded. Prenatal exposure to PRO and DBP resulted in a dose-dependent reduction in AGD, increased retention of nipples, delay in PPS, increased incidence of malformations, and reduced reproductive tissue weights. Further, these changes were accurately predicted by use of dose-additive models of cumulative toxicity, a result that would not be in line with traditional mixtures toxicology. However, these two chemicals induce the same androgen-mediated toxicity; namely, reduce the amount of AR bound to the endogenous ligand (T or DHT). Therefore, the androgen-dependent gene signaling pathways are affected by both chemicals. These data have implications for both basic mixture research and risk assessment of chemical mixtures, and support inclusion of chemicals in cumulative risk assessments that disrupt differentiation of the same fetal tissues at different sites along androgen signaling pathways.